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In Vivo1
,
Departments of
*
Pathology,
Microbiology and Immunology, and
Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599; and
§
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(MIP-1) in vivo, we
used MIP-1-deficient (MIP-1-/-) mice as
donors and as recipients in adoptive transfer experiments after a
lethal infection with Listeria monocytogenes (LM).
Unexpectedly, we found that the production of MIP-1 by
CD8+ T cells was critical in this system, as the cells from
MIP-1-/- mice primed with LM were significantly less
effective in protecting naive mice against a lethal infection by LM
than were the CD8+ T cells from wild-type (wt) mice.
This requirement for donor T cell production of MIP-1 was confirmed
by the observation that wt donor T cells do not mediate protection when
coadministered with an anti-MIP-1 polyclonal antiserum.
Production of MIP-1 by the recipient mice was not required for
protection, because wt and MIP-1-/- recipients were
equally well protected by wt T cells. A 2- to 3-fold decrease in the
number of transferred lymphocytes was seen in the spleens of mice
receiving T cells from MIP-1-/- mice compared with
those receiving wt T cells. In addition, CD8+ T cells from
MIP-1-/- mice had a reduced ability to kill
LM-infected target cells in vitro. These findings demonstrate that T
cell production of MIP-1 is required for clearance of an
intracellular pathogen in vivo. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Leukocyte recruitment to inflamed tissues is a multistep process that includes the initial adherence of leukocytes to the vascular endothelium, followed by diapedesis into the underlying tissue, and then migration toward target cells within the parenchyma. These events are mediated by interactions between the molecules displayed on the leukocyte cell surface and those presented on the endothelium and subvascular tissue. Members of the selectin family and their cognate receptors promote the initial tethering of leukocytes to the endothelium, whereas integrins and their receptors mediate the firm adherence of the leukocytes to the vessel wall (reviewed in 3). The molecular interactions that direct the subsequent steps of diapedesis and leukocyte migration within the extravascular tissue are less well understood, but are thought to involve chemokines and their receptors.
Chemokines comprise a large family of structurally homologous, low-m.w. secreted proteins that induce chemotaxis of specific classes of leukocytes in vitro (4) and can mediate the tissue-specific recruitment of neutrophils and monocytes in transgenic mice (5, 6). Chemokines also possess other activities, including the capacity to induce the proliferation and activation of T lymphocytes in vitro (7). Although their expression in inflammatory settings is well documented, knowledge of the function of chemokines in vivo is limited. In particular, the requirement for the production of individual chemokines in inflammatory responses and in pathogen clearance is not clear, and the biologically relevant cellular sources of chemokines have not been investigated.
Macrophage inflammatory protein-1
(MIP-1)4 is a CC chemokine
that has multiple activities in vitro, including chemotaxis of
monocytes and CD8+ T lymphocytes (8, 9), activation of
basophils and mast cells (10), and enhancement of the proliferation and
activation of T lymphocytes in vitro (7). MIP-1 is also an important
mediator of inflammation in vivo, because gene-targeted mice that
cannot produce MIP-1 (MIP-1-/- mice) have a reduced
mononuclear cell content in virus-infected tissues compared with that
seen in wild-type (wt) mice (11). However, the mechanism of action of
MIP-1 has not been elucidated, and it is not clear whether any of
the cell types that express this chemokine in vitro (i.e., macrophages
(12), T lymphocytes (13, 14), and fibroblasts (15)) are biologically
relevant sources in vivo.
Murine listeriosis is a suitable model to investigate the relevant
cellular sources of MIP-1 in vivo because the clearance of the
causative organism, Listeria monocytogenes (LM), is mediated
primarily by macrophages and T cells, the cell lineages which respond
to MIP-1 in chemotaxis assays. Activated macrophages are necessary
to control the early stages of a primary infection, whereas
CD8+ T cells are important at later stages (reviewed in
Refs. 16 and 17). The function of T cells in listeriosis can be studied
directly in adoptive transfer experiments, in which naive recipient
mice receiving a lethal dose of LM survive when infused with T
lymphocytes from an immunized donor mouse (18). Here, we have used
MIP-1-deficient mice or wt mice as recipients and as donors of T
lymphocytes to determine the biological relevance of different sources
of MIP-1. We show that donor T lymphocytes, but not cells in the
recipient mouse, must produce MIP-1 for these T cells to migrate to
the infected spleen and provide immunity against LM.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The derivation of MIP-1 gene-disrupted mice has been
described previously (11). In the present studies, two different kinds
of mice carrying the MIP-1 disruption were used: mice of a mixed
genetic background derived from the two inbred strains, 129 Ola and
C57BL/6, and mice in which the MIP-1 gene disruption had been
backcrossed onto the C57BL/6 background for seven generations. Similar
results were obtained with both sets of mice. Age-matched mice having a
similar genetic background but having an intact MIP-1gene were used as controls. The mice were maintained under
specific pathogen-free conditions and were used when they were between
7 and 16 wk of age. All experiments were conducted according to
institutional guidelines for the University of North Carolina at Chapel
Hill.
Bacteria
LM (strain EGD) was prepared as described previously (19). Briefly, bacteria were grown in trypticase soy broth, and the approximate concentration of logarithmically growing cultures was determined by spectrophotometric analysis. Bacteria were resuspended in nonbacteriostatic saline, and equal volumes were injected into the lateral tail vein of each mouse. A more precise estimate of the number of organisms injected was determined by plating various dilutions of the bacterial suspension on trypticase soy agar and quantifying colonies the following day.
RNA isolation and analysis
Splenic tissue from LM-infected mice was homogenized in RNA
stat-60 (Tel Test, Friendswood, TX) or Tri-reagent (Molecular Research
Center, Cincinnati, OH) using a Polytron tissue homogenizer
(Brinkmann, Westbury, NY). Total RNA was extracted according to
the manufacturer’s instructions, and 5 mg of total RNA was
electrophoresed through a 0.8% agarose gel containing formaldehyde.
The RNA was then transferred to a Hybond-N+ nylon membrane
(Amersham, Arlington Heights, IL) by Northern blotting, and the
membrane was probed with [32P]deoxyCTP-labeled
MIP-1 cDNA prepared using a random-primed DNA labeling kit
(Boehringer Mannheim, Mannheim, Germany). Similar experiments
were performed in which blots were probed with 32P-labeled
TNF-, IFN-
, and IL-1ß DNA.
Adoptive transfer experiments
To obtain donor T cells, C57BL/6J mice or
MIP-1-/- mice were injected with 5 x
102 to 1 x 103 CFU of LM. Mice were
sacrificed at day 7 postinfection (p.i.), and their spleens were
removed, pooled, and minced with a razor blade in RPMI 1640 medium
containing 10% (v/v) FBS, 2 mM L-glutamine, and 5 x
10-5 M 2-ME. RBCs were lysed in ACK lysis buffer
(0.15 M NH4Cl, 1 mM KHCO3, and 0.1 mM
Na2 EDTA). The remaining splenocytes were washed
twice in PBS and resuspended in nonbacteriostatic saline. These cells
were enriched for T lymphocytes by passing the preparation through a
nylon wool column. Flow cytometric analysis revealed that 90% of the
prepared cells stained for the T lymphocyte surface marker CD3, 3% for
the B lymphocyte marker CD19, and 7% for the monocyte lineage marker
F4/80.
CD8+ T cells were prepared from bulk splenocytes using anti-CD8 Abs coupled to magnetic beads (Miltenyi Biotec, Bergisch Gladbach, Germany) according to the manufacturer’s instructions. Flow cytometric analyses of these preparations showed that >98% of the transferred cells stained for the CD8 marker.
Recipient mice received either 1 x 107 nylon wool-purified T lymphocytes or 2 x 106 CD8+-enriched T cells, followed 30 min later by an injection of 5 x 104 to 1 x 105 CFU of LM. In survival assays, the mice were followed for 10 days. Moribund animals were euthanized to minimize unnecessary suffering. These animals were included in the group that did not survive.
To measure CFU in the infected recipients, mice were sacrificed at 40 h p.i.; their spleens were minced using fine scissors or a razor blade in PBS containing 0.1% Triton X-100. Serial dilutions of this splenic homogenate were spread onto trypticase soy agar plates, and bacterial colonies were counted on the following day.
Blocking Ab experiments
A polyclonal anti-MIP-1 antiserum raised in immunized
rabbits has been described previously (20). The antiserum was injected
i.p. (0.5 ml) at 1 h before an i.v. injection of 5 x
104 CFU LM. A second injection of the antiserum was given
at 48 h p.i.
Flow cytometry
B6.PL-Thy1a/Cy (Thy 1.1) mice were
purchased from The Jackson Laboratory (Bar Harbor, ME). Donor wt and
MIP-1-/- mice (Thy 1.2) were infected with 1 x
103 LM and sacrificed at day 7. T cells were prepared from
bulk splenocytes with nylon wool columns and infused via the lateral
tail vein into Thy 1.1 recipient mice that had been infected 45 min
previously with 1 x 105 LM. Mice were sacrificed at
48 h posttransfer, their spleens were removed, and single-cell
suspensions of splenocytes were generated. These cells were stained
with phycoerythrin-conjugated anti-CD8 (PharMingen,
San Diego, CA) and FITC-conjugated Thy 1.2 mAbs (PharMingen) for
30 min at 4°C and subsequently analyzed on a FACScan (Becton
Dickinson, Mountain View, CA) using Cicero Software (Cytomation,
Fort Collins, CO). A total of 10,000 events were analyzed.
CTL assays
MIP-1-/- and wt mice were infected with
103 CFU of LM. The mice were sacrificed at 8 days p.i., and
CD8+ lymphocytes were isolated from bulk splenocytes using
anti-CD8-coupled magnetic beads. The cells were stimulated twice
with irradiated (2500 cGy) C57BL/6J splenocytes that had been infected
with LM as described previously (19). Flow cytometric analysis revealed
that 98–99% of these cells stained for the marker CD8. No
CD4-staining cells were detected. These T cells were tested for lytic
activity on IC21 cells in a standard 51Cr release assay.
All samples were run in duplicate. The experiment was repeated five
times with qualitatively similar results. Percent lysis was measured as
follows: 100 x ([sample (cpm) - spontaneous (cpm)]/[total
(cpm) - spontaneous (cpm)]).
Total counts were measured from target cells lysed in 5% Triton X-100. Spontaneous activity was measured from supernatants of wells with target cells but no effector cells. The spontaneous release for all target cells was <30% of total activity.
Statistics
The Mann-Whitney rank sum test was used to calculate the statistical significance of differences between groups of recipient mice in the number of recovered LM CFU. Fischer’s exact test was used to calculate p values for survival experiments.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine whether MIP-1 is expressed in mice infected with
LM, Northern blot analysis was performed on RNA extracted from their
spleens at various times p.i. A low level of MIP-1 expression was
seen at days 1, 2, and 4 p.i., with much higher levels seen at day
7 p.i. (Fig. 1
).
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, and TNF- are three cytokines that have been shown
previously to be important in clearing LM (21, 22, 23). Northern blot
analysis of each of these cytokines revealed that their expression
levels in the wt and MIP-1-/--infected mice are
indistinguishable at days 1, 2, and 4 (data not shown).
Naive MIP-1-/- mice are protected from a lethal
challenge of LM by adoptive transfer of immune wt T cells
The high expression of MIP-1 seen at day 7 p.i. coincided
with the previously described onset of LM-specific CTL activity in
infected mice (24), suggesting that MIP-1 may be important for the T
cell-mediated clearance of this pathogen. However, this possibility
cannot be easily tested in this type of experiment because macrophages
as well as T cells are able to clear LM-infected cells during primary
infections. In addition, both of these cell types produce MIP-1 in
vitro. Therefore, to study the role of MIP-1 in the T cell-mediated
clearance of LM, we performed a series of adoptive transfer experiments
in which the survival of naive mice receiving a lethal challenge of
bacteria was dependent upon the protective activity of T cells
transferred from an immunized donor mouse.
We first tested whether T lymphocytes from immunized wt mice were
protective when transferred to mice that cannot express MIP-1. T
cells prepared from the spleens of immunized wt mice were separately
injected into naive wt and naive MIP-1-/- recipient
mice immediately before their challenge with a lethal inoculum of LM
(5 x 104 CFU). Infected mice that did not receive T
cells succumbed to the infection, whereas both the wt and the
MIP-1-/- recipients were protected by the transferred
wt T cells (Fig. 2A). These
results show that primed wt T cells can protect recipient mice, and
that the production of MIP-1 by the recipient mouse is not essential
for this protection.
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in the recipient mouse had
an effect on the function of the transferred wt T cells that was not
detected in the survival assay, additional experiments were conducted
in which the recipient mice were sacrificed at 40 h posttransfer
and their spleens were analyzed for LM CFU. No increase in CFU was seen
in the spleens of the MIP-1-/- recipient mice compared
with the wt recipients. Rather, the MIP-1-/- mice had
fewer bacteria (p < 0.01) than wt recipients
(Fig. 2
B).
MIP-1-/- T cells have a severely reduced capacity
to protect naive wt mice
T lymphocytes have been shown previously to produce MIP-1 in
vitro (13, 14, 25). To determine whether MIP-1 production by the
transferred T cells is required for their ability to mediate the
clearance of LM, we compared the protective abilities of T cells
harvested from wt and MIP-1-/- mice. As described
previously, T cells from the wt donor mice protected the infected wt
recipients. However, as shown in Fig. 3A, T cells from the
MIP-1-/- donor mice had a dramatically reduced
capacity to protect the infected recipient mice
(p < 0.001).
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-/- have an
increased bacterial load compared with mice receiving wt cells. As
shown in Fig. 3B, mice receiving MIP-1-/-
donor T cells had significantly more CFU (p =
0.03) than mice receiving wt donor T cells. Thus, as measured by both
survival and bacterial load, T cells from MIP-1-/-
mice do not clear LM in vivo as efficiently as T cells from wt mice.
Adoptive T cell transfer of protection against listeriosis is mediated
predominantly by CD8+ T lymphocytes (26, 27). Therefore, we
performed additional experiments in which CD8+ T cells were
used as the donor cells rather than unfractionated T cells. As shown in
Fig. 3C, the results of these experiments were qualitatively
similar to those obtained when unfractionated T cells were used; in
total, 9 of 12 mice receiving wt CD8+ T cells survived,
whereas only 2 of 12 mice receiving primed MIP-1-/-
CD8+ T cells survived (p = 0.012).
Next, we tested whether the reduced effectiveness of
MIP-1-/- T cells could be overcome if a larger number
of cells were transferred. As described previously, when
107 T cells were transferred, the MIP-1-/-
cells were less effective than wt cells: only 1 of 14 infected
recipient mice receiving MIP-1-/- CD8+ T
cells survived, whereas 5 of 6 mice receiving wt cells survived. When
108 MIP-1-/- T cells were transferred, 9
of 14 recipient mice survived, indicating that this 10-fold increase in
these donor cells can partially compensate for their reduced
effectiveness.
Anti-MIP-1 antiserum blocks the in vivo function of wt
Listeria-specific T cells
The inability of the MIP-1-/- T cells to
efficiently clear bacteria from the infected recipient mice suggested
that a T cell-specific production of MIP-1 by the donor cells was
required after their transfer to the infected recipient mice. If this
is so, an antiserum raised against MIP-1 should be able to abrogate
the ability of the primed wt T cells to protect naive mice from the
bacterial challenge. Therefore, we injected a rabbit anti-MIP-1
polyclonal antiserum and primed wt donor T cells into infected wt
recipients. All recipient mice (eight of eight) receiving both
the anti-MIP-1 antiserum and the wt T cells died or were
moribund by 60 h (Fig. 4). In
contrast, only one death was seen among six recipients receiving both a
control normal rabbit serum and wt T lymphocytes (p
= 0.003).
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-/- T cells in the spleen
We subsequently investigated whether the inability of the
MIP-1-/- donor T cells to efficiently clear the
bacteria was associated with a reduced number of donor cells in the
spleens of the recipient mice compared with that seen with the wt donor
cells. We used Thy 1.1+ wt mice as recipients to allow
detection of the donor wt and MIP-1-/- T cells (both
Thy 1.2+). Flow cytometric analyses of the donor cells
performed at 48 h posttransfer revealed that mice receiving the
MIP-1-/- donor T cells had 3- to 5-fold fewer
CD8+, Thy 1.2+ cells in their spleens than mice
receiving wt donor T cells (Fig. 5).
Interestingly, the Thy1.2+ cells detected in the spleens of
mice receiving the wt T cells were almost entirely CD8+,
whereas in mice receiving MIP-1-/- T cells, the
majority of Thy1.2+ donor cells did not stain for CD8.
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-/- T cells have a slightly reduced cytolytic
activity in vitro
MIP-1 can induce the activation and proliferation of T cells in
vitro (7). To investigate whether T cells from
MIP-1-/- mice are able to lyse LM-infected target
cells in vitro, we derived T cell lines from infected wt mice and
infected MIP-1-/- mice and compared these lines for
their ability to lyse LM-infected macrophages. Both wt and
MIP-1-/- T cells were able to lyse
51Cr-labeled LM-infected macrophage target cells in an
MHC-restricted, Ag-specific manner, although the
MIP-1-/- cells were 25–50% less efficient than the
wt cells (Fig. 6). This difference,
although small, was reproducibly seen in five separate experiments
using independently derived cell lines.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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that mediate T lymphocyte function in vivo. Several
lines of evidence show that T cells, in particular CD8+ T
cells, are a biologically relevant source of MIP-1. First,
CD8+ T lymphocytes from MIP-1-/- mice were
significantly less effective than their wt counterparts in promoting
the clearance of LM from infected naive mice. Second, the ability of wt
T cells to clear the bacteria was abrogated by the injection of
anti-MIP-1-specific Abs into wt recipient mice. Third, infected
MIP-1-/- recipients and wt recipient mice were equally
well protected by the wt donor T cells, demonstrating that endogenous
production of MIP-1 by the recipient mice was not required for the
protective function of the donor T cells.
There are several possible explanations for this demonstrated
requirement for CD8+ cell-produced MIP-1. First, it may
be required to recruit or to maintain recruited CD8+ T
effector cells to the infected spleen. In support of this possibility,
fewer donor CD8+ T cells were detected in the spleens of
mice receiving MIP-1-/- donor T cells than in mice
receiving wt donor T cells. In contrast, the number of cells that did
not express CD8 was not reduced, suggesting that MIP-1 may
specifically recruit CD8+ cells in vivo. This observation
is consistent with the finding that CD8+ cells are much
more responsive to MIP-1 in chemotaxis assays than are
CD4+ cells (8, 9).
A second possible function of the CD8+ T cell-produced
MIP-1 may be to participate in the activation of these cells by an
autocrine mechanism. We observed a small (25–50%) but reproducible
decrease in the in vitro cytotoxic activity of T cells cultured from
the MIP-1-/- mice compared with T cells cultured from
wt mice. This reduced cytolytic activity could result from the absence
of MIP-1 during the assay itself or from a slight reduction in the
priming of T cells in the donor MIP-1-/- mice.
Regardless, it is unlikely that this difference is sufficient to
account entirely for the dramatic difference seen in vivo between the
wt and MIP-1-/- T cells. Moreover, the ability
of the anti-MIP-1 antiserum to block the protective function of
wt donor T cells indicates that MIP-1 must be produced after
transfer of these cells to the recipient mice.
It is possible that the T cell-produced MIP-1 induces the expression
of other cytokines that in turn mediate bacterial clearance. We did not
detect any differences between the infected wt and
MIP-1-/- mice in their levels of mRNA encoding
IL-1ß, TNF-, or IFN-, three cytokines that are important for
macrophage-mediated clearance of LM. However, we cannot exclude the
possibility that cytokines other than those tested may be induced by
MIP-1 and are required for macrophage-mediated clearance.
Expression of MIP-1 by CD8+ T cells has been observed in
vitro (13, 14, 25) and in vivo (28), but the biological relevance of
this expression has not been demonstrated until now. Interestingly,
MIP-1 expression can be induced in T cells by anti-CD3 Ab, and
this induction is dependent upon CD28/B7 costimulation (25). In
addition, we have recently found using Listeria-specific
cell lines that the production of MIP-1 by CD8+ T cells
is dependent upon the presence of Ag (J.S.S. et al., unpublished
data). MIP-1 has also been implicated in the recruitment of
CD8+ T cells in vivo (29). Thus, an attractive hypothesis
is that MIP-1 is produced in vivo by CD8+ T cells upon
their recognition of the Ag presented on pathogen-infected cells, and
this production results in a local gradient of the chemokine with the
highest concentration near the infected cells. This gradient could
direct the migration of other T lymphocytes to these "marked" foci
of infected tissue. These recruited cells would in turn participate in
an escalating production of more chemokine, serving to amplify the
inflammatory response. In this regard, it is noteworthy that the
MIP-1-/- recipient mice receiving wt T cells had
significantly fewer bacteria than the wt recipients. The absence in
these mutant mice of MIP-1 expression in cells other than the
Ag-stimulated donor CD8+ T cells may actually increase the
effectiveness of the suggested CD8+ T cell-generated
gradient of MIP-1, resulting in a more efficient recruitment of
nearby effector cells and consequently in increased clearance of the
bacteria.
In summary, we have conducted experiments in which
MIP-1-/- mice were used as donors and as recipients of
adoptively transferred CD8+ T lymphocytes to demonstrate
that CD8+ T cells are a biologically relevant source of
MIP-1. The general experimental design used here is likely to be
useful in identifying biologically relevant sources of other secreted
molecules.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Immunology, Schering Plough Research Institute, Kenilworth, NJ 07033.
3 Address correspondence and reprint requests to Dr. Jonathan S. Serody, Campus Box 7295, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599-7295. E-mail address:
4 Abbreviations used in this paper: MIP, macrophage inflammatory protein; wt, wild-type; LM, Listeria monocytogenes; p.i., postinfection.
Received for publication November 11, 1998. Accepted for publication February 11, 1999.
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References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and MIP-1ß. Science 260:355. (MIP-1) and MIP-1ß chemokines attract distinct populations of lymphocytes. J. Exp. Med. 177:1821. and monocyte chemoattractant peptide-1 elicit immediate and late cutaneous reactions and activate mast cells in vivo. J. Immunol. 152:1298.[Abstract]
for an inflammatory response to viral infection. Science
269.
, interleukin-8, and RANTES. Eur. J. Immunol. 25:751.[Medline]
, and MIP-1ß as the major HIV-suppressive factors produced by CD8+ T cells. Science 270:1811. by inflammatory granuloma fibroblasts. J. Pathol. 144:711.
in Schistosoma mansoni egg-induced granulomatous inflammation. J. Exp. Med. 177:1551. receptor. Science 259:1742. mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature 364:798.[Medline]
, and MIP-1ß in rat experimental autoimmune encephalomyelitis by in situ hybridization. J. Neuroimmunol. 77:17.[Medline]
. J. Immunol. 159:360.[Abstract]
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Y. Miura, C. J. Thoburn, E. C. Bright, W. Chen, S. Nakao, and A. D. Hess Cytokine and chemokine profiles in autologous graft-versus-host disease (GVHD): interleukin 10 and interferon gamma may be critical mediators for the development of autologous GVHD Blood, September 18, 2002; 100(7): 2650 - 2658. [Abstract] [Full Text] [PDF]
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Y. Belkaid, E. Von Stebut, S. Mendez, R. Lira, E. Caler, S. Bertholet, M. C. Udey, and D. Sacks CD8+ T Cells Are Required for Primary Immunity in C57BL/6 Mice Following Low-Dose, Intradermal Challenge with Leishmania major J. Immunol., April 15, 2002; 168(8): 3992 - 4000. [Abstract] [Full Text] [PDF]
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A. Nansen, J. P. Christensen, S. O. Andreasen, C. Bartholdy, J. E. Christensen, and A. R. Thomsen The role of CC chemokine receptor 5 in antiviral immunity Blood, February 15, 2002; 99(4): 1237 - 1245. [Abstract] [Full Text] [PDF]
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 S. W. Chensue Molecular Machinations: Chemokine Signals in Host-Pathogen Interactions Clin. Microbiol. Rev., October 1, 2001; 14(4): 821 - 835. [Abstract] [Full Text] [PDF]
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 D. M. Lindell, T. J. Standiford, P. Mancuso, Z. J. Leshen, and G. B. Huffnagle Macrophage Inflammatory Protein 1{alpha}/CCL3 Is Required for Clearance of an Acute Klebsiella pneumoniae Pulmonary Infection Infect. Immun., October 1, 2001; 69(10): 6364 - 6369. [Abstract] [Full Text] [PDF]
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E. J. McMahon, D. N. Cook, K. Suzuki, and G. K. Matsushima Absence of Macrophage-Inflammatory Protein-1{alpha} Delays Central Nervous System Demyelination in the Presence of an Intact Blood-Brain Barrier J. Immunol., September 1, 2001; 167(5): 2964 - 2971. [Abstract] [Full Text] [PDF]
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W. Zhong, A. D. Roberts, and D. L. Woodland Antibody-Independent Antiviral Function of Memory CD4+ T Cells In Vivo Requires Regulatory Signals from CD8+ Effector T Cells J. Immunol., August 1, 2001; 167(3): 1379 - 1386. [Abstract] [Full Text] [PDF]
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 D. N. Cook, S.-C. Chen, L. M. Sullivan, D. J. Manfra, M. T. Wiekowski, D. M. Prosser, G. Vassileva, and S. A. Lira Generation and Analysis of Mice Lacking the Chemokine Fractalkine Mol. Cell. Biol., May 1, 2001; 21(9): 3159 - 3165. [Abstract] [Full Text]
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 B. C. Biedermann Vascular Endothelium: Checkpoint for Inflammation and Immunity Physiology, April 1, 2001; 16(2): 84 - 88. [Abstract] [Full Text] [PDF]
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M. A. Olszewski, G. B. Huffnagle, R. A. McDonald, D. M. Lindell, B. B. Moore, D. N. Cook, and G. B. Toews The Role of Macrophage Inflammatory Protein-1{alpha}/CCL3 in Regulation of T Cell-Mediated Immunity to Cryptococcus neoformans Infection J. Immunol., December 1, 2000; 165(11): 6429 - 6436. [Abstract] [Full Text] [PDF]
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J. S. Serody, S. E. Burkett, A. Panoskaltsis-Mortari, J. Ng-Cashin, E. McMahon, G. K. Matsushima, S. A. Lira, D. N. Cook, and B. R. Blazar T-lymphocyte production of macrophage inflammatory protein-1alpha is critical to the recruitment of CD8+ T cells to the liver, lung, and spleen during graft-versus-host disease Blood, November 1, 2000; 96(9): 2973 - 2980. [Abstract] [Full Text] [PDF]
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 I. E. A. Flesch, D. Stober, R. Schirmbeck, and J. Reimann Monocyte inflammatory protein-1{alpha} facilitates priming of CD8+ T cell responses to exogenous viral antigen Int. Immunol., September 1, 2000; 12(9): 1365 - 1370. [Abstract] [Full Text] [PDF]
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M. J. Cameron, G. A. Arreaza, M. Grattan, C. Meagher, S. Sharif, M. D. Burdick, R. M. Strieter, D. N. Cook, and T. L. Delovitch Differential Expression of CC Chemokines and the CCR5 Receptor in the Pancreas Is Associated with Progression to Type I Diabetes J. Immunol., July 15, 2000; 165(2): 1102 - 1110. [Abstract] [Full Text] [PDF]
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V. P. Badovinac and J. T. Harty Adaptive Immunity and Enhanced CD8+ T Cell Response to Listeria monocytogenes in the Absence of Perforin and IFN-{gamma} J. Immunol., June 15, 2000; 164(12): 6444 - 6452. [Abstract] [Full Text] [PDF]
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C. Casoli, E. Vicenzi, A. Cimarelli, G. Magnani, P. Ciancianaini, E. Cattaneo, P. Dall'Aglio, G. Poli, and U. Bertazzoni HTLV-II down-regulates HIV-1 replication in IL-2-stimulated primary PBMC of coinfected individuals through expression of MIP-1alpha Blood, May 1, 2000; 95(9): 2760 - 2769. [Abstract] [Full Text] [PDF]
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